{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:02:34Z","timestamp":1789671754573,"version":"4.0.1"},"reference-count":34,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T00:00:00Z","timestamp":1728432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dr. Georg E. und Marianne Kosing-Stiftung","award":["INST 37\/1049-1"],"award-info":[{"award-number":["INST 37\/1049-1"]}]},{"name":"DFG-funded NGS Competence Center T\u00fcbingen","award":["INST 37\/1049-1"],"award-info":[{"award-number":["INST 37\/1049-1"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","award":["INST 37\/1049-1"],"award-info":[{"award-number":["INST 37\/1049-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pathogenic variants in the ryanodine receptor 1 (RYR1) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype\u2013phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic RYR1 variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic RYR1 variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient\u2019s phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous RYR1 variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype\u2013phenotype correlations.<\/jats:p>","DOI":"10.3390\/ijms251910867","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T12:22:48Z","timestamp":1728476568000},"page":"10867","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Compound Heterozygous RYR1 Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive RYR1-Related Myopathy"],"prefix":"10.3390","volume":"25","author":[{"given":"S\u00f6ren","family":"Jan\u00dfen","sequence":"first","affiliation":[{"name":"Department of Neuropediatrics, University Children\u2019s Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leoni S.","family":"Erbe","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Kneifel","sequence":"additional","affiliation":[{"name":"Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1782-4642","authenticated-orcid":false,"given":"Matthias","family":"Vorgerd","sequence":"additional","affiliation":[{"name":"Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"D\u00f6ring","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof P.","family":"Lubieniecki","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna M.","family":"Lubieniecka","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3858-9872","authenticated-orcid":false,"given":"Wanda M.","family":"Gerding","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2209-0580","authenticated-orcid":false,"given":"Nicolas","family":"Casadei","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Applied Genomics, University T\u00fcbingen, 72074 T\u00fcbingen, Germany"},{"name":"NGS Competence Center T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4017-940X","authenticated-orcid":false,"given":"Anne-Katrin","family":"G\u00fcttsches","sequence":"additional","affiliation":[{"name":"Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Heyer","sequence":"additional","affiliation":[{"name":"Institute for Pediatric Radiology, Katholisches Klinikum Bochum, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"L\u00fccke","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, University Children\u2019s Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"},{"name":"Center for Rare Diseases Ruhr (CeSER), 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6139-788X","authenticated-orcid":false,"given":"Hoa Huu Phuc","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany"},{"name":"Center for Rare Diseases Ruhr (CeSER), 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia","family":"K\u00f6hler","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, University Children\u2019s Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"},{"name":"Center for Rare Diseases Ruhr (CeSER), 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Hoffjan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, Germany"},{"name":"Center for Rare Diseases Ruhr (CeSER), 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chang, X., Wei, R., Wei, C., Liu, J., Qin, L., Yan, H., Ma, Y., Wang, Z., and Xiong, H. 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